This invention relates to novel compositions and to methods for inhibiting the development of tolerance to and dependence on drugs of the opioid type without substantial alteration of their analgesic effects. More particularly, the invention relates to compositions comprising opioid drugs and certain peptides and to administration of these compositions to obtain the desired inhibiting effect. In a specific aspect, the invention relates to pretreatment with certain peptides followed by daily administration of the peptide during chronic morphine treatment.
It is known that certain neurohypophyseal hormones, their analogs and disulfide-containing cyclic fragments of these hormones, facilitate development of physical dependence on and tolerance to actions of morphine (van Ree, J. M. and de Wied, D., Life Sci., 19, 1331-1340[1976]). Several of these peptides, notably vasopressin and its analogs, can modify various aspects of behaviour including acquisition and extinction of conditioned responses in lower species as well as of memory in man. In addition, non-disulfide-containing linear hormone fragments, such as MSH-release inhibiting factor, prolyl-leucyl-glycylamide, N-carbobenzoxyprolyl-leucyl-glycylamide, enzymatically stable cyclo(leucyl-glycine), and prolyl-arginyl-glycylamide also exhibit these effects Walter, R., et al., Proc. Natl. Acad. Sci. USA, 72, 4180-4184[1975]).
Recently, in comparing the relative potencies of these peptides on facilitating the development of physical dependence on and tolerance to morphine it was found that not only oxytocin and 8-arginine vasotocin are more effective than 8-arginine vasopressin but that MSH-release inhibiting factor Pro-Leu-Gly-NH.sub.2 and cyclo(Leu-Gly) are as effective as oxytocin in these tests (van Rec, J. M. and de Wied, D., Life Sci., 19, 1331--1340[1976]).